Host resistance to visceral leishmaniasis: prevalence and prevention

ABSTRACT

Visceral leishmaniasis (VL) is a chronic parasitic disease caused by the vector-borne Leishmania donovani and Leishmania (L.) infantum chagasi parasites. The disease affects about 12 million humans in more than 90 countries worldwide. If not treated, the visceral form of Leishmania infection is potentially fatal, yielding about 50000 deaths per year. In the vertebrate host, the Leishmania species causing VL spread systematically to propagate in macrophage reservoirs distributed in the tissues of internal organs, primarily the liver, spleen, bone marrow and the lymph nodes. The infection is associated with evolved mechanisms from the parasite to subvert the host immune system in order to establish a persistent infection. Currently, efforts are being deployed to develop new anti-leishmanial therapies in VL combining immunomodulatory treatment regimens that burst the host immune responses together with leishmanicidal drugs that target the parasite growth. Discoveries in this field are discussed in this article.

KEYWORDS:

• Infectious disease
• leishmania
• visceral leishmaniasis
• immunology
• therapy

Financial & competing interests disclosure

This work was supported by grants from Conselho Nacional de Desenvolvimento Científico e Tecnológico do Brasil (CNPq) to A Morrot and CG Freire-de-Lima, Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAP ERJ). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• Visceral leishmaniasis is the most severe form of leishmaniasis, responsible for an estimated 200,000–400,000 infections each year worldwide, yielding about 50,000 deaths per year.

• In endemic areas, infected individuals with Leishmania strains causing visceral leishmaniasis show a continuum of immune responses from protective to non-protective immunity.

• Individuals who acquire protective immunity against visceral leishmaniasis show a strong T helper type 1 (Th1) CD4⁺ T cell responses with ability to kill intracellular Leishmania parasites.

• The pathogenesis of visceral leishmaniasis is associated with expression of high levels of the immunosuppressive cytokine IL-10, responsible to mediate parasite growth in macrophages.

• Patients with increased levels of immunosuppression are poor responders to leishmanicidal drugs, showing a higher susceptibility to visceral dissemination of the parasite.

• Multidrug unresponsiveness is associated to parasite resistance to drug therapies targeting common aspects of parasite biology.

• Leishmanicidal drugs directly targeting the parasite in combination with therapies to potentiate host immune responses such as vaccine-based immunotherapies is considered to be an effective way to control visceral leishmaniasis.